Protein palmitoylation in cancer: molecular functions and therapeutic potential

Zhou, Binhui; Hao, Qianyun; Liang, Yinming; Kong, Eryan

doi:10.1002/1878-0261.13308

Cited by 36 publications

(21 citation statements)

References 155 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the past decade, the importance of protein palmitoylation in tumorigenesis has become evident. It plays a crucial role in various critical aspects of cancer, such as cell proliferation and survival, cell invasion and metastasis, as well as the modulation of antitumor immune responses . We have reported here that orlistat and palmostatin B are nanomolar inhibitors of PPT1 which are structurally related usingTanimoto similarity (MACCS fingerprints) of 0.65, and both molecules contain a hydrophobic tail and a β lactone ring.…”

Section: Discussionmentioning

confidence: 91%

“…Palmostatin B is a nonspecific depalmitoylation inhibitor that primarily inhibits the acyl-protein thioesterases APT-1 and APT-2, which, like PPT1, can catalyze the removal of S-palmitoylation from protein substrates . It was earlier demonstrated that the combination of palmostatin B with the FLT3 inhibitor gilteritinib significantly suppressed FLT3-ITD-mediated signaling and leukemia progression .…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Identification of New Modulators and Inhibitors of Palmitoyl-Protein Thioesterase 1 for CLN1 Batten Disease and Cancer

Puhl,

Raman,

Havener

et al. 2024

ACS Omega

View full text Add to dashboard Cite

Palmitoyl-protein thioesterase 1 (PPT1) is an understudied enzyme that is gaining attention due to its role in the depalmitoylation of several proteins involved in neurodegenerative diseases and cancer. PPT1 is overexpressed in several cancers, specifically cholangiocarcinoma and esophageal cancers. Inhibitors of PPT1 lead to cell death and have been shown to enhance the killing of tumor cells alongside known chemotherapeutics. PPT1 is hence a viable target for anticancer drug development. Furthermore, mutations in PPT1 cause a lysosomal storage disorder called infantile neuronal ceroid lipofuscinosis (CLN1 disease). Molecules that can inhibit, stabilize, or modulate the activity of this target are needed to address these diseases. We used PPT1 enzymatic assays to identify molecules that were subsequently tested by using differential scanning fluorimetry and microscale thermophoresis. Selected compounds were also tested in neuroblastoma cell lines. The resulting PPT1 screening data was used for building machine learning models to help select additional compounds for testing. We discovered two of the most potent PPT1 inhibitors reported to date, orlistat (IC 50 178.8 nM) and palmostatin B (IC 50 11.8 nM). When tested in HepG2 cells, it was found that these molecules had decreased activity, indicating that they were likely not penetrating the cells. The combination of in vitro enzymatic and biophysical assays enabled the identification of several molecules that can bind or inhibit PPT1 and may aid in the discovery of modulators or chaperones. The molecules identified could be used as a starting point for further optimization as treatments for other potential therapeutic applications outside CLN1 disease, such as cancer and neurological diseases.

show abstract

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Identification of New Modulators and Inhibitors of Palmitoyl-Protein Thioesterase 1 for CLN1 Batten Disease and Cancer

Puhl,

Raman,

Havener

et al. 2024

ACS Omega

View full text Add to dashboard Cite

show abstract

“…Fast expanding in the research field of understanding the roles of protein palmitoylation in different types of human malignancies has been achieved in the past decades [39][40][41], however, it was revealed that the linkage between palmitoylation and HCC is relatively weak as compared to other tumor types, e.g. breast cancer, prostate cancer, colorectal cancer, leukemia, melanoma, pancreatic cancer and NSCLC [20,23,[42][43][44][45][46][47][48]. Our current study strengthened the connection that AEG-1, a key driver of HCC, is palmitoylated, which negatively regulates its protein stability via proteasome mediated degradation pathway; inhibiting AEG-1 palmitoylation enhances its binding to SND1 and thus the RISC activity, the latter may downregulate the mRNA level of several tumor suppressors as PTEN/TGFB2 and therefore promotes HCC progression.…”

Section: Discussionmentioning

confidence: 99%

“…To date, 23 mammalian palmitoyl-transferases, namely zDHHCs [16] and 5 depalmitoylating enzymes including APT1/2, PPT1/2 and ABHD17a [17][18][19] have been identified. The link between palmitoylation and various types of human malignancies has been firmly established by the findings that many oncogenes and tumor suppressors are palmitoylated [8,[20][21][22][23], yet, such relationship is labile in HCC.…”

Section: Introductionmentioning

confidence: 99%

The palmitoylation of AEG-1 dynamically modulates the progression of hepatocellular carcinoma

et al. 2022

View full text Add to dashboard Cite

Rationale: Protein palmitoylation is tightly related to tumorigenesis or tumor progression as many oncogenes or tumor suppressors are palmitoylated. AEG-1, an oncogene, is commonly elevated in a variety of human malignancies, including hepatocellular carcinoma (HCC). Although AEG-1 was suggested to be potentially modified by protein palmitoylation, the regulatory roles of AEG-1 palmitoylation in tumor progression of HCC has not been explored. Methods: Techniques as Acyl-RAC assay and point mutation were used to confirm that AEG-1 is indeed palmitoylated. Moreover, biochemical experiments and immunofluorescent microscopy were applied to examine the cellular functions of AEG-1 palmitoylation in several cell lines. Remarkably, genetically modified knock-in (AEG-1-C75A) and knockout (Zdhhc6-KO) mice were established and subjected to the treatment of DEN to induce the HCC mice model, through which the roles of AEG-1 palmitoylation in HCC is directly addressed. Last, HCQ, a chemical compound, was introduced to prove in principal that elevating the level of AEG-1 palmitoylation might benefit the treatment of HCC in xenograft mouse model. Results: We showed that AEG-1 undergoes palmitoylation on a conserved cysteine residue, Cys-75. Blocking AEG-1 palmitoylation exacerbates the progression of DEN-induced HCC in vivo . Moreover, it was demonstrated that AEG-1 palmitoylation is dynamically regulated by zDHHC6 and PPT1/2. Accordingly, suppressing the level of AEG-1 palmitoylation by the deletion of Zdhhc6 reproduces the enhanced tumor-progression phenotype in DEN-induced HCC mouse model. Mechanistically, we showed that AEG-1 palmitoylation adversely regulates its protein stability and weakens AEG-1 and staphylococcal nuclease and tudor domain containing 1 (SND1) interaction, which might contribute to the alterations of the RISC activity and the expression of tumor suppressors. For intervention, HCQ, an inhibitor of PPT1, was applied to augment the level of AEG-1 palmitoylation, which retards the tumor growth of HCC in xenograft model. Conclusion: Our study suggests an unknown mechanism that AEG-1 palmitoylation dynamically manipulates HCC progression and pinpoints that raising AEG-1 palmitoylation might confer beneficial effect on the treatment of HCC.

show abstract

“…[10] Altered APT1 activity has been associated with cancer, neurodegenerative diseases, and cardiovascular disorders. [11] Targeted modulation of APT1 could potentially be explored in therapy aimed at addressing these conditions. [9b,12] Moreover, serine hydrolases have been extensively studied using ABPP, benefiting from a comprehensive proteomics toolbox for their analysis.…”

mentioning

confidence: 99%

Design and Evaluation of PROTACs Targeting Acyl Protein Thioesterase 1

Carvalho,

Sousa,

Zaidman

et al. 2024

ChemBioChem

View full text Add to dashboard Cite

PROTAC linker design remains mostly an empirical task. We employed the PRosettaC computational software in the design of sulfonyl‐fluoride‐based PROTACs targeting acyl protein thioesterase 1 (APT1). The software efficiently generated ternary complex models from empirically‐designed PROTACs and suggested alkyl linkers to be the preferred type of linker to target APT1. Western blotting analysis revealed efficient degradation of APT1 and activity‐based protein profiling showed remarkable selectivity of an alkyl linker‐based PROTAC amongst serine hydrolases. Collectively, our data suggests that combining PRosettaC and chemoproteomics can effectively assist in triaging PROTACs for synthesis and providing early data on their potency and selectivity.

show abstract

Protein palmitoylation in cancer: molecular functions and therapeutic potential

Cited by 36 publications

References 155 publications

Identification of New Modulators and Inhibitors of Palmitoyl-Protein Thioesterase 1 for CLN1 Batten Disease and Cancer

Identification of New Modulators and Inhibitors of Palmitoyl-Protein Thioesterase 1 for CLN1 Batten Disease and Cancer

The palmitoylation of AEG-1 dynamically modulates the progression of hepatocellular carcinoma

Design and Evaluation of PROTACs Targeting Acyl Protein Thioesterase 1

Contact Info

Product

Resources

About